Cigarette smoking dramatically changes the architecture of the airway epithelium relevant to chronic obstructive pulmonary disease (COPD), the major smoking-induced lung disorder, for which no disease-modifying therapies that reduce mortality are available. The major airway epithelial remodeling (AER) phenotypes induced by cigarette smoking are basal cell (BC) and mucous cell hyperplasia, squamous metaplasia, reduced number of ciliated cells, shorter cilia, and decreased junctional barrier integrity. However, specific mechanisms responsible for common pathogenesis of smoking-associated AER phenotypes in the human airways are unknown. Based on the knowledge that epidermal growth factor receptor (EGFR) signaling is altered by cigarette smoke, and our previous observations that EGFR is highly expressed in airway BC, the stem/progenitor cells of airway epithelium, and mediates squamous metaplasia and epithelial leak, we have further focused on the EGFR signaling as a central element in the pathogenesis of all major smoking-induced AER phenotypes. Our preliminary studies have shown that: (1) EGFR ligand amphiregulin (AREG) is up-regulated in the AER areas of the airway epithelium of smokers and COPD smokers; (2) smoking-associated factors (EGF, TGF-beta, cigarette smoke extract) induce AREG expression in vitro in airway BC undergoing squamous differentiation; (3) AREG, by acting on human airway BC in vitro, promotes AER phenotypes, including BC- and mucous cell hyperplasia, decreased ciliated cell differentiation and junctional barrier integrity; (4) AREG-induced effects are distinct from those evoked by EGF: EGF does not induce hyperplasia, while AREG induces delayed and sustained EGFR activation associated with the maintenance of the receptor on the BC surface; (5) AREG promotes its own expression in airway BC. These data led to central hypothesis of this study, i.e., that up-regulation and unique signaling of AREG in airway BC stem/progenitor cells mediate smoking-induced COPD-relevant remodeling of the airway epithelium. To test this hypothesis, 3 Specific aims are proposed. Aim 1. Identify the common molecular pathways activated in human airway BC by smoking-induced factors responsible for generation of AREG-producing cells and increased AREG expression in the human airway epithelium. Aim 2. Determine specific molecular mechanisms of AREG signaling in airway BC that mediate AREG-induced smoking-associated airway epithelial remodeling (AER) phenotypes. Aim 3. Evaluate the hypothesis that inhibition of mechanisms of AREG up-regulation and signaling in airway BC will prevent or suppress the development of smoking-induced airway epithelial remodeling (AER). If proven correct, this study will provide the basis for novel therapeutic strategies to prevent and treat airway epithelial disordering in COPD by targeting smoking-induced AREG up-regulation and signaling in airway BC stem/progenitor cells.